These studies were designed to determine whether hydroxyurea, an S phase ctyotoxic drug, would cause significant augmentation of fetal hemoglobin in patients with sickle cell anemia and beta thalassemia. Increases in HbF could be documented by sensitive immunological methods in approximately half of the patients with sickle cell anemia but no increase in HbF synthesis or red cell production was observed in two patients with thalassemia. Hence, our attention was redirected to testing several drugs singly, or in combination, in experimental animals in an effort to define a clinically useful regimen. 5-Azacytidine, hydroxyurea, and cytosine arabinoside each cause an increase in HbF in baboons and Rhesus monkeys although 5-azacytidine is approximately two fold more active than the other two drugs. DMSO alone has no effect on HbF production but it appears to augment the increment seen following 5-azacytidine administration. Additional drugs will be tested during the next year in an effort to further explore the clinical potential and mechanism of action of these agents effect of an inducer of hemoglobin synthesis (dimethyl sulfoxide) that may augment the fetal hemoglobin response to 5-azacytidine.